The cause of systemic lupus erythematosus (SLE) is unknown; recent work has focused on the possibility that atypical or chronic virus infection underlies the immunologic abnormalities. Studies of the immunologic disease, much like SLE, of New Zealand mice indicate an oncornavirus is involved. "Virus-like" inclusions are found in SLE, but their nature is unknown. Virus isolation and seroepidemiologic studies have not implicated a specific virus. New methods have been successful in isolating viruses from human neoplastic and chronic neurologic diseases. They have not been systematically applied to SLE, where isolation of the etiologic agent would advance our understanding of pathogenesis, so that treatment and prevention should be possible. Similar advances would be likely to follow in commoner connective tissue diseases like rheumatoid arthritis. It is proposed to apply systematically to cell cultures of SLE tissues both new virus isolation techniques (cocultivation, Sendai-virus and lysolecithin-induced cell fusion, induction with iododeoxyuridine and similar agents, radiolabelling - as used to detect oncornaviruses in man and other species) and indirect immunofluorescence, electron microscopy and other standard methods, a combination which would detect most known viruses. It is also proposed to test urines from SLE patients for papova- and other viruses, using cell cultures and hemagglutination, because one of the papovaviruses isolated from progressive multifocal leukoencephalopathy came from a patient with SLE. Most infections with this agent may be inapparent, since antibody is widespread, but they might initiate SLE in predisposed individuals. Any agents isolated would be fully characterized and animals inoculated to develop models of human SLE in which treatment and prevention could be evaluated prior to trial in man.